Obesity is a heritable disease that affects millions of people, is disproportionately prevalent in the Pima Indians of Southwestern Arizona, and has serious health consequences. The main scientific goals of the Obesity & Diabetes Clinical Research Section (ODCR) are to study (1) mechanisms of weight gain in Pimas and other human populations and (2) the pathophysiology of type 2 diabetes mellitus (T2DM) in non-obese and obese individuals. 1. Mechanisms of weight gain in Pima Indians and other human populations. Bodyweight may be influenced by both peripheral hormonal signals and by neuroregulation of satiety and food intake. We have found that certain peripheral hormones from the gastrointestinal system (pancreatic polypeptide and ghrelin) and from adipose tissue (adiponectin and resistin) may influence long term control of bodyweight. Our previous studies using positron emission tomography, a non invasive radiological technique that allows us to study patterns of brain activity associated with consumption of food, have found specific areas of the brain related to satiety and hunger which may differ between lean and obese individuals. Using another non-invasive brain imaging technique, magnetic resonance imaging, which allows us to examine morphological differences in cerebral gray matter, we found differences in gray matter density in areas related to taste and reward processing between lean and obese individuals. Future studies examining whether these changes in gray matter density are altered by weight loss are planned. 2.Pathophysiology of T2DM in non-obese and obese individuals. The adipose tissue is now recognized as an organ that secretes a large number of proteins, which are collectively referred to as adipokines. We have continued to uncover evidence that an adipokine-induced activation of the immune system may mediate the effect of over nutrition on insulin resistance and later development of T2DM. In particular, we now have evidence that increased adipocyte production of macrophage migration inhibiting factor (MIF), a cytokine with chemo attractant and proinflammatory properties, may be an important link between obesity and insulin resistance in adult Pimas. We are currently running a placebo controlled clinical trial designed to test if a short treatment with an anti-inflammatory drug improves insulin resistance in non-diabetic obese individuals. Past work demonstrated that fat cell size is an important predictor of development of diabetes. Our further work in this area demonstrates that fat cell size is related to excess fat accumulation in muscle and in particular in liver and may be mediated by the adipocyte hormone adiponectin. Increased liver fat accumulation is related to worsening insulin sensitivity. In utero exposure to diabetes is a potent risk factor for the development of early onset type 2 diabetes. We have found that offspring of diabetic pregnancies have reduced insulin secretion in response to a mixed meal compared to offspring of non-diabetic pregnancies, and that in utero exposure to diabetes is a significant determinant of higher systolic blood pressure and hemoglobin A1C during childhood.